YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage.
YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage.
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DOI：
10.1038/onc.2015.219
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发表时间：
2016-03-24
期刊：
影响因子：
8
通讯作者：
Pili R
中科院分区：
文献类型：
--
作者：
Ciamporcero E;Shen H;Ramakrishnan S;Yu Ku S;Chintala S;Shen L;Adelaiye R;Miles KM;Ullio C;Pizzimenti S;Daga M;Azabdaftari G;Attwood K;Johnson C;Zhang J;Barrera G;Pili R
目前肌肉侵袭性尿路上皮细胞癌（UCC）的标准治疗是手术配合围手术期铂基化疗。UCC对以顺铂为基础的方案敏感，但最终会发生获得性耐药，并且一部分肿瘤具有内在耐药。因此，对针对化疗耐药UCC的新治疗方法的需求尚未得到满足。yes相关蛋白（YAP）是一种转录共激活因子，与膀胱癌进展和卵巢癌顺铂耐药相关。相反，YAP已被证明在非小细胞肺癌中诱导DNA损伤相关的凋亡。然而，尚无关于YAP在UCC化疗耐药中的作用的数据报道。因此，我们利用最近建立的两种患者来源的异种移植模型研究了YAP在UCC对化疗反应中的潜在双重作用。YAP的组成表达和激活与体外和体内顺铂敏感性呈负相关。YAP过表达保护UCC细胞，而YAP敲低则通过增加DNA损伤和凋亡的积累使UCC细胞对化疗和放疗敏感。此外，用维替波芬抑制YAP可抑制肿瘤细胞增殖，恢复对顺铂的敏感性。此外，核YAP表达与接受围手术期化疗的UCC患者预后不良相关。综上所述，这些结果表明YAP激活在UCC治疗中发挥了保护作用，并代表了一个增强DNA损伤方式抗肿瘤作用的药理学靶点。
Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non-small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knock-down sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC.